P377: GENETIC CHARACTERISTICS AND CD7-CAR-T THERAPY OF TRAD::MYC TRANSLOCATION POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS
Authors: T. Wang, J. Ni, H. Zhang, S. Hui, T. Liu, X. Zhang, G. Zhang, X. Ma, X. Wang, Y. Zhang, Q. Zhang, H. Liu
Journal: HemaSphere (2022)

Background:TRAD::MYC is a recurrent but rare translocation in leukemia and lacks relevantreports. Aims: To investigate the genetic characteristics of acute lymphoblastic leukemia (ALL) with TRAD::MYC translocation and the clinical outcome of chimeric antigen receptor T cells (CAR-T) therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: A retrospective analysis was performed of 5,450 patients with ALL admitted to our hospital from Apr. 1, 2016, to Dec. 31, 2021. Cases positive for t(8;14)(q24.1;q11.2) in karyotype analysis were selected, TRAD::MYC translocation and CDKN2A/B gene deletion were confirmed by fluorescence in situ hybridization (FISH). The TRAD::MYC positive cases were further screened for a panel of 36 common leukemia fusion genes (FGs), RNA-seq for comprehensive analysis of FGs, and mutation screening of a panel of 86 leukemia driver genes. Results: A total of 12 cases were TRAD::MYC positive, 9 males and 3 females, aged 3-28 years (median 15 years), 9 children (<18 years old) and 3 adults. The diagnosis included 11 T-ALL and 1 B-ALL, and 7 cases (63.6%) manifested high white blood cells (180-486.18×109/L) at the onset. Nine cases had karyotype results at the initial onset, of which three were positive for t(8;14)(q24.1;q11.2), and the rest 6 acquired this translocation at relapse. In the 3 cases with no karyotype results at the initial onset, t(8;14)(q24.1;q11.2) was detected in relapse specimens. Of the 12 cases, 11 showed additional karyotype abnormalities in t(8;14)(q24.1;q11.2) positive specimens. FISH confirmed the involvement of TRAD and MYC genes corresponding to t(8;14)(q24.1;q11.2) in all 12 cases, and CDKN2A/B gene loss was detected in 4 (33%) cases. All cases were screened for fusion genes, and RNA-seq was performed in five cases. Six cases were positive for driver FGs, including 3 STIL::TAL1, 1 KMT2A::AF9 in the B-ALL case, 1 CTCF::NFATC3, and 1 ZC3HAV1::ABL2. Six cases (50%) were positive for PTEN mutation and 3 positive for FBXW7 mutation, other mutated genes including NOTCH1, TP53, CCND3, etc. Eleven cases were followed up for 6-67 months (median 11 months), and 8 died during the follow-up period. Eight cases (72.7%) experienced central nervous system (CNS) leukemia, and 3 had mediastinal invasion. All patients relapsed after chemotherapy, and the leukemia cells proliferated rapidly. Six cases received CD7-CAR-T therapy, and all achieved disease remission after CAR-T cell infusion, of which 1 died from secondary severe lung infection and 2 died from relapse. Four cases underwent allo-HSCT, including 2 salvage transplantation and 2 bridging transplantation after CD7-CAR-T regimen. All 3 cases that remained alive received CD7- CAR-T therapy, 2 of which were bridged to allo-HSCT. Image:Summary/Conclusion: Recurrent t(8;14)(q24.1;q11.2)/TRAD::MYC have a low incidence, mainly in T-ALL cases, but can also be seen in B-ALL. More than half of cases acquired the translocation at relapse and in some cases accompanied with other driver FGs in T-ALL such as STIL::TAL1, KMT2A fusions, and ABL family gene fusions. TRAD::MYC translocation confers aberrant MYC expression and hyperproliferative of tumor cells. Half cases were also accompanied by PTEN mutation, which further adversely affected the prognosis. In these cases, the response to conventional chemotherapy is extremely poor and prone to early relapse, and CNS infiltration is common. CD7-CAR-T regimen bridging to allo-HSCT might be a promising therapeutic strategy for better survival in this subgroup, and the long-term outcomes remain to be further investigated.